Applied Biochemistry and Biotechnology

, Volume 186, Issue 1, pp 145–160 | Cite as

Synthetic Dibenzoxanthene Derivatives Induce Apoptosis Through Mitochondrial Pathway in Human Hepatocellular Cancer Cells

  • Zhi Jia
  • Hui Hui Yang
  • Yun-Jun LiuEmail author
  • Xiu-Zhen WangEmail author


A new series of dibenzoxanthenes 4a4f were synthesized through the nucleophilic substitution and characterized by NMR and MS spectra. Their antitumor activity was screened by MTT assay. Compounds (except 4b and 4c) displayed strong growth inhibitory effects against chosen five tumor cells under light irradiation. The molecular mechanism of compound-induced cell apoptosis was investigated by AO/EB staining, comet assay, DCFH-DA, JC-1 fluorescent probe, and western blotting. Compounds induced the apoptosis of HepG2 cells and DNA damage. Location assay showed that compounds entered the nucleus of tumor cells. Furthermore, it was found that compounds induced loss of mitochondrial membrane potential, acceleration of ROS production, and activation of caspse-3, caspase-7, and caspase-9 proteins. Compounds upregulated the expression of pro-apoptotic Bim and Bax and downregulated the expression of anti-apoptotic Bcl-xl and Bcl-2. These results indicated that compounds induced the apoptosis of HepG2 cells through ROS-mediated mitochondrial pathway. The induction of apoptosis by dibenzoxanthenes may provide an important mechanism for their cancer chemopreventive function.


Dibenzoxanthenes Nucleophilic substitution Cytotoxicity Comet assay Apoptosis 



This work was supported by the Priority Academic Program Development of Guangdong Higher Education Institutions (2013LYM0047), the Natural Science Foundation of Guangdong Province (No. 2016A030313728) and the National Nature Science Foundation of China (No. 81403111), and Project of Innovation for Enhancing Guangdong Pharmaceutical University, Provincial Experimental Teaching Demonstration Center of Chemistry & Chemical Engineering.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interest.


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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.College of PharmacyGuangdong Pharmaceutical UniversityGuangzhouPeople’s Republic of China
  2. 2.Guangdong Engineering Research Center for Lead Compounds & Drug DiscoveryGuangzhouPeople’s Republic of China

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